Menin is a tumor suppressor required to prevent multiple endocrine neoplasia in humans. Mammalian menin protein is associated with chromatin modifying complexes and has been shown to bind a number of nuclear proteins, including the transcription factor JunD. Menin shows bidirectional effects acting positively on c-Jun and negatively on JunD. We have produced protein null alleles of Drosophila menin (mnn1) and have over expressed the Mnn1 protein. Flies homozygous for protein-null mnn1 alleles are viable and fertile. Localized over-expression of Mnn1 causes defects in thoracic closure, a phenotype that sometimes results from insufficient Jun activity. We observed complex genetic interactions between mnn1 and jun in different developmental settings. Our data support the idea that one function of menin is to modulate Jun activity in a manner dependent on the cellular context.
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"GAL4 targeted RNAi knockdown technology (Brand and Perrimon 1993) was used to create transgenic flies capable of inducible reduction of endogenous Dmel\ELP3 in specific cell and tissue-types of choice. This strategy has been successfully used for functional analysis of numerous genes in Drosophila (Cerrato et al. 2006; Zhu et al. 2007; Rushton et al. 2009). The Dmel\ELP3/RNAi construct was created by selecting a 650 bp RNAi non-conserved target sequence specific for Dmel\ELP3 (Fig. 1a and b) shown by Basic local alignment search tool (BLAST) searches to exhibit non-redundancy within the genome. "
[Show abstract][Hide abstract]ABSTRACT: J. Neurochem. (2010) 115, 493–504.
The histone acetyltransferase Elp3 (Elongator Protein 3) is the catalytic subunit of the highly conserved Elongator complex. Elp3 is essential for the complex functions of Elongator in both the nucleus and cytoplasm of neurons, including the epigenetic control of neuronal motility genes and the acetylation of α-tubulin that affects axonal branching and cortical neuron migration. Accordingly, misregulation of Elp3 has been implicated in human disorders that specifically affect neuronal function, including familial dysautonomia, a disease characterized by degeneration of the sensory and autonomic nervous system, and the motor neuron degenerative disorder amyotrophic lateral sclerosis. These studies underscore the importance of Elp3 in neurodevelopment and disease, and the need to further characterize the multiple nuclear and cytoplasmic based roles of ELP3 required for neurogenesis in animal models, in vivo. In this report, we investigate the behavioral and morphological consequences that result from targeted reduction of ELP3 specifically in the developing Drosophila nervous system. We demonstrate that loss of Elp3 during neurodevelopment leads to a hyperactive phenotype and sleep loss in the adult flies, a significant expansion in synaptic bouton number and axonal length and branching in the larval neuromuscular junction as well as the misregulation of certain genes known to be involved in these processes. Our results uncover a novel role for Elp3 in the regulation of synaptic bouton expansion during neurogenesis that may be linked with a requirement for sleep.
Preview · Article · Oct 2010 · Journal of Neurochemistry
[Show abstract][Hide abstract]ABSTRACT: AP-1, an immediate-early transcription factor comprising heterodimers of the Fos and Jun proteins, has been shown in several animal models, including Drosophila, to control neuronal development and plasticity. In spite of this important role, very little is known about additional proteins that regulate, cooperate with, or are downstream targets of AP-1 in neurons. Here, we outline results from an overexpression/misexpression screen in Drosophila to identify potential regulators of AP-1 function at third instar larval neuromuscular junction (NMJ) synapses. First, we utilize >4000 enhancer and promoter (EP) and EPgy2 lines to screen a large subset of Drosophila genes for their ability to modify an AP-1-dependent eye-growth phenotype. Of 303 initially identified genes, we use a set of selection criteria to arrive at 25 prioritized genes from the resulting collection of putative interactors. Of these, perturbations in 13 genes result in synaptic phenotypes. Finally, we show that one candidate, the GSK-3beta-kinase homolog, shaggy, negatively influences AP-1-dependent synaptic growth, by modulating the Jun-N-terminal kinase pathway, and also regulates presynaptic neurotransmitter release at the larval neuromuscular junction. Other candidates identified in this screen provide a useful starting point to investigate genes that interact with AP-1 in vivo to regulate neuronal development and plasticity.
[Show abstract][Hide abstract]ABSTRACT: The cloning of the MEN1 gene in 1997 led to the characterization of menin, the protein behind the multiple endocrine neoplasia Type 1 syndrome. Menin, a novel nuclear protein with no homology to other gene products, is expressed ubiquitously. MEN1 missense mutations are dispersed along the coding region of the gene but are more common in the most conserved regions. Likewise, domains of protein interaction often correspond to the more conserved segments of menin. These protein interactions are generally facilitated by multiple domains or encompass a large portion of menin. The exception to this rule is a small stretch of amino acids mediating the interaction of menin with the mSin3A corepressor and histone deacetylase complexes. The C-terminal region of menin harbors several nuclear localization signals that play redundant functions in the localization of menin to the nuclear compartment. The nuclear localization signals are also important for the interaction of menin with the nuclear matrix. Menin is the target of several kinases and a candidate substrate of the ATM/ATR kinases, implying a role for this tumor suppressor in the DNA damage response. Menin is highly conserved from Drosophila to human but is absent in the nematode and in yeast.
No preview · Article · Jan 2009 · Advances in Experimental Medicine and Biology